Dynamic cranial nerve stimulation based on brain state determination from cardiac data

ABSTRACT

A method of treating a medical condition in a patient using an implantable medical device, comprising providing an electrical signal generator; providing at least a first electrode operatively coupled to the electrical signal generator and to a vagus nerve of the patient; sensing cardiac data of the patient; determining at least a first cardiac parameter based upon said cardiac data; setting at least a first value; declaring an unstable brain state of a patient from said at least a first cardiac parameter and said at least a first value; and adjusting the at least a first value. Also, a computer readable program storage device encoded with instructions that, when executed by a computer, performs the method. In addition, the implantable medical device used in the method.

BACKGROUND OF THE INVENTION

This invention relates generally to medical device systems and, moreparticularly, to medical device systems for applying electrical signalsto a cranial nerve for the treatment of various medical conditionsexhibiting unstable brain states as determined by analysis of data froma patient's cardiac cycle.

Many advancements have been made in treating medical conditionsinvolving or mediated by the neurological systems and structures of thehuman body. In addition to drugs and surgical intervention, therapiesusing electrical signals for modulating electrical activity of the bodyhave been found to be effective for many medical conditions. Inparticular, medical devices have been effectively used to delivertherapeutic electrical signals to various portions of a patient's body(e.g., the vagus nerve) for treating a variety of medical conditions.Electrical signal therapy may be applied to a target portion of the bodyby an implantable medical device (IMD) that is located inside thepatient's body or, alternatively, may be applied by devices locatedexternal to the body. In addition, some proposed devices include acombination of implanted and external components.

The vagus nerve (cranial nerve X) is the longest nerve in the humanbody. It originates in the brainstem and extends, through the jugularforamen, down below the head, to the abdomen. Branches of the vagusnerve innervate various organs of the body, including the heart, thestomach, the lungs, the kidneys, the pancreas, and the liver. In view ofthe vagus nerve's many functions, a medical device such as an electricalsignal generator has been coupled to a patient's vagus nerve to treat anumber of medical conditions. In particular, electrical signal therapyfor the vagus nerve, often referred to as vagus nerve stimulation (VNS),has been approved in the United States and elsewhere to treat epilepsyand depression. In particular, application of an electrical signal tothe vagus nerve is thought to modulate some areas in the brain that areprone to seizure activity.

Implantable medical devices (IMDs) have been effectively used to delivertherapeutic stimulation to various portions of the human body (e.g., thevagus nerve) for treating a variety of diseases. As used herein,“stimulation” or “stimulation signal” refers to the application of anelectrical, mechanical, magnetic, electromagnetic, photonic, audioand/or chemical signal to a neural structure in the patient's body. Thesignal is an exogenous signal that is distinct from the endogenouselectrical, mechanical, and chemical activity (e.g., afferent and/orefferent electrical action potentials) generated by the patient's bodyand environment. In other words, the stimulation signal (whetherelectrical, mechanical, magnetic, electromagnetic, photonic, audio orchemical in nature) applied to the nerve in the present invention is asignal applied from an artificial source, e.g., a neurostimulator.

A “therapeutic signal” refers to a stimulation signal delivered to apatient's body with the intent of treating a medical condition byproviding a modulating effect to neural tissue. The effect of astimulation signal on neuronal activity is termed “modulation”; however,for simplicity, the terms “stimulating” and “modulating”, and variantsthereof, are sometimes used interchangeably herein. In general, however,the delivery of an exogenous signal itself refers to “stimulation” ofthe neural structure, while the effects of that signal, if any, on theelectrical activity of the neural structure are properly referred to as“modulation.” The modulating effect of the stimulation signal upon theneural tissue may be excitatory or inhibitory, and may potentiate acuteand/or long-term changes in neuronal activity. For example, the“modulating” effect of the stimulation signal to the neural tissue maycomprise one more of the following effects: (a) initiation of an actionpotential (afferent and/or efferent action potentials); (b) inhibitionor blocking of the conduction of action potentials, whether endogenousor exogenously induced, including hyperpolarizing and/or collisionblocking, (c) affecting changes in neurotransmitter/neuromodulatorrelease or uptake, and (d) changes in neuro-plasticity or neurogenesisof brain tissue.

In some embodiments, electrical neurostimulation may be provided byimplanting an electrical device underneath the skin of a patient anddelivering an electrical signal to a nerve such as a cranial nerve. Inone embodiment, the electrical neurostimulation involves sensing ordetecting a body parameter, with the electrical signal being deliveredin response to the sensed body parameter. This type of stimulation isgenerally referred to as “active,” “feedback,” or “triggered”stimulation. In another embodiment, the system may operate withoutsensing or detecting a body parameter once the patient has beendiagnosed with a medical condition that may be treated byneurostimulation. In this case, the system may apply a series ofelectrical pulses to the nerve (e.g., a cranial nerve such as a vagusnerve) periodically, intermittently, or continuously throughout the day,or over another predetermined time interval. This type of stimulation isgenerally referred to as “passive,” “non-feedback,” or “prophylactic,”stimulation. In yet another type of stimulation, both passivestimulation and feedback stimulation may be combined, in whichelectrical signals are delivered passively according to a predeterminedduty cycle, and also in response to a sensed body parameter indicating aneed for therapy. The electrical signal may be applied by a pulsegenerator that is implanted within the patient's body. In anotheralternative embodiment, the signal may be generated by an external pulsegenerator outside the patient's body, coupled by an RF or wireless linkto an implanted electrode or an external transcutaneous neurostimulator(TNS).

Generally, neurostimulation signals that perform neuromodulation aredelivered by the IMD via one (i.e., unipolar) or more (i.e., bipolar)leads. The leads generally terminate at their distal ends in one or moreelectrodes, and the electrodes, in turn, are electrically coupled totissue in the patient's body. For example, a number of electrodes may beattached to various points of a nerve or other tissue inside or outsidea human body for delivery of a neurostimulation signal.

Conventional vagus nerve stimulation (VNS) usually involves non-feedbackstimulation characterized by a number of parameters. Specifically,conventional vagus nerve stimulation usually involves a series ofelectrical pulses in bursts defined by an “on-time” and an “off-time.”During the on-time, electrical pulses of a defined electrical current(e.g., 0.5-2.0 milliamps) and pulse width (e.g., 0.25-1.0 milliseconds)are delivered at a defined frequency (e.g., 20-30 Hz) for the on-timeduration, usually a specific number of seconds, e.g., 7-60 seconds. Thepulse bursts are separated from one another by the off-time, (e.g., 14seconds-5 minutes) in which no electrical signal is applied to thenerve. The on-time and off-time parameters together define a duty cycle,which is the ratio of the on-time to the sum of the on-time andoff-time, and which describes the percentage of time that the electricalsignal is applied to the nerve. It will be appreciated that calculationof duty cycle should also include any ramp-up and/or ramp-down time.

In conventional VNS, the on-time and off-time may be programmed todefine an intermittent pattern in which a repeating series of electricalpulse bursts are generated and applied to the vagus nerve 127. Eachsequence of pulses during an on-time may be referred to as a “pulseburst.” The burst is followed by the off-time period in which no signalsare applied to the nerve. The off-time is provided to allow the nerve torecover from the stimulation of the pulse burst, and to conserve power.If the off-time is set at zero, the electrical signal in conventionalVNS may provide continuous stimulation to the vagus nerve.Alternatively, the idle time may be as long as one day or more, in whichcase the pulse bursts are provided only once per day or at even longerintervals. Typically, however, the ratio of “off-time” to “on-time” mayrange from about 0.5 to about 10.

Although neurostimulation has proven effective in the treatment of anumber of medical conditions, including epilepsy, it would be desirableto further enhance and optimize a therapeutic regimen comprisingneurostimulation for this purpose. For example, it may be desirable toprovide an active therapeutic regimen at times when an unstable brainstate occurs. (An “unstable brain state” will be defined below). It mayalso be desirable to declare an unstable brain state as occurring, basedon data routinely collected from extracranial sources. It may further bedesirable to adjust the sensitivity of declaring when an unstable brainstate occurs, to make a declaration of an unstable brain state more orless likely for different patients, for the same patient at differenttimes of day, month, or year, or under other conditions.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to an implantablemedical device (IMD) to treat a medical condition in a patient,comprising an electrical signal generator; at least a first electrodeoperatively coupled to the electrical signal generator and to a vagusnerve of the patient; a cardiac data sensing module capable of sensingcardiac data from the patient; an unstable brain state declarationmodule comprising a cardiac module capable of determining at least afirst cardiac parameter based upon sensed cardiac data from the patient;and a value setting module for setting at least a first value to be usedby the unstable brain state declaration module; wherein the unstablebrain state declaration module is capable of declaring an unstable brainstate of a patient from said at least a first cardiac parameter and saidat least a first value and the value setting module is capable ofadjusting said at least a first value.

In one embodiment, the present invention relates to a method of treatinga medical condition in a patient using an implantable medical device,comprising providing an electrical signal generator; providing at leasta first electrode operatively coupled to the electrical signal generatorand to a vagus nerve of the patient; sensing cardiac data of thepatient; determining at least a first cardiac parameter based upon saidcardiac data; setting at least a first value; declaring an unstablebrain state of a patient from said at least a first cardiac parameterand said at least a first value; and adjusting said at least a firstvalue.

In one embodiment, the present invention relates to a computer readableprogram storage device encoded with instructions that, when executed bya computer, performs a method of treating a medical condition in apatient using an implantable medical device, comprising providing anelectrical signal generator; providing at least a first electrodeoperatively coupled to the electrical signal generator and to a vagusnerve of the patient; sensing cardiac data of the patient; determiningat least a first cardiac parameter based upon said cardiac data; settingat least a first value; declaring an unstable brain state of a patientfrom said at least a first cardiac parameter and said at least a firstvalue; and adjusting said at least a first value.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be understood by reference to the followingdescription taken in conjunction with the accompanying drawings, inwhich like reference numerals identify like elements, and in which:

FIGS. 1A-1C provide stylized diagrams of an implantable medical deviceimplanted into a patient's body for providing an electrical signal to aportion of the patient's body, in accordance with one illustrativeembodiment of the present invention;

FIG. 2 illustrates a block diagram depiction of the implantable medicaldevice of FIG. 1, in accordance with one illustrative embodiment of thepresent invention;

FIG. 3 illustrates an exemplary waveform sequence of a cardiac cycle ofa human being as measured by an electrocardiogram (EKG);

FIG. 4 illustrates a flowchart depiction of a method in accordance withan illustrative embodiment of the present invention; and

FIG. 5 illustrates a flowchart depiction of further steps of a method inaccordance with an illustrative embodiment of the present invention.

While the invention is susceptible to various modifications andalternative forms, specific embodiments thereof have been shown by wayof example in the drawings and are herein described in detail. It shouldbe understood, however, that the description herein of specificembodiments is not intended to limit the invention to the particularforms disclosed, but on the contrary, the intention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the invention as defined by the appended claims.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Illustrative embodiments of the invention are described herein. In theinterest of clarity, not all features of an actual implementation aredescribed in this specification. In the development of any such actualembodiment, numerous implementation-specific decisions must be made toachieve the design-specific goals, which will vary from oneimplementation to another. It will be appreciated that such adevelopment effort, while possibly complex and time-consuming, wouldnevertheless be a routine undertaking for persons of ordinary skill inthe art having the benefit of this disclosure.

This document does not intend to distinguish between components thatdiffer in name but not function. In the following discussion and in theclaims, the terms “including” and “includes” are used in an open-endedfashion, and thus should be interpreted to mean “including, but notlimited to.” Also, the term “couple” or “couples” is intended to meaneither a direct or an indirect electrical connection. “Direct contact,”“direct attachment,” or providing a “direct coupling” indicates that asurface of a first element contacts the surface of a second element withno substantial attenuating medium there between. The presence of smallquantities of substances, such as bodily fluids, that do notsubstantially attenuate electrical connections does not vitiate directcontact. The word “or” is used in the inclusive sense (i.e., “and/or”)unless a specific use to the contrary is explicitly stated.

The term “electrode” or “electrodes” described herein may refer to oneor more stimulation electrodes (i.e., electrodes for delivering anelectrical signal generated by an IMD to a tissue), sensing electrodes(i.e., electrodes for sensing a physiological indication of a patient'sbody), and/or electrodes that are capable of delivering a stimulationsignal, as well as performing a sensing function.

“Cardiac cycle” refers to one complete PQRSTU interval of the patient'sheart functioning, ending with the P wave of the next succeeding cardiaccycle. “Interbeat interval” refers to the time period between apredetermined point in a first cardiac cycle of the patient and the samepredetermined point in the immediately succeeding cardiac cycle of thepatient, for example an R-R interval, a P-P interval, or a T-T interval.Interbeat intervals may comprise a single interval or a time-varyingstatistic, such as a moving average (either simple or weighted) ofseveral consecutive intervals. “Cardiac period” is a length of timebetween a first point in the cardiac cycle of the patient and a second,later point. Exemplary points include a P-wave, a Q-wave, an R-wave, anS-wave, a T-wave, and a U-wave of the cardiac cycle, which can bereadily identified by electrocardiography (EKG) or other techniques ofmonitoring the electrical activity of the heart.

Any method step referring to the storing, recalling, manipulating, orchanging of data, a parameter, or a value is to be understood asreferring to making physical changes in an apparatus, such as animplantable medical device or an external apparatus in communicationwith an implantable medical device; such method steps do not refer toany purely mental step performed in the mind of a human being.

Cranial nerve stimulation has been proposed to treat a number of medicalconditions pertaining to or mediated by one or more neural structures ofthe body, including epilepsy and other movement disorders, depression,anxiety disorders and other neuropsychiatric disorders, dementia, headtrauma and traumatic brain injury, coma, obesity, eating disorders,sleep disorders, cardiac disorders (such as congestive heart failure andatrial fibrillation), hypertension, endocrine disorders (such asdiabetes and hypoglycemia), and pain syndromes (including migraineheadache and fibromyalgia), among others. See, e.g., U.S. Pat. Nos.4,867,164; 5,299,569; 5,269,303; 5,571,150; 5,215,086; 5,188,104;5,263,480; 6,587,719; 6,609,025; 5,335,657; 6,622,041; 5,916,239;5,707,400; 5,231,988; and 5,330,515. Despite the numerous disorders forwhich cranial nerve stimulation has been proposed or suggested as atreatment option, the fact that detailed neural pathways for many (ifnot all) cranial nerves remain relatively unknown, makes predictions ofefficacy for any given disorder difficult or impossible. Moreover, evenif such pathways were known, the precise stimulation parameters thatwould modulate particular pathways relevant to a particular disordergenerally cannot be predicted.

In one embodiment, the present invention provides a method of treating amedical condition. The medical condition can be selected from the groupconsisting of epilepsy, neuropsychiatric disorders (including but notlimited to depression), eating disorders/obesity, traumatic braininjury/coma, addiction disorders, dementia, sleep disorders, pain,migraine, fibromyalgia, endocrine/pancreatic disorders (including butnot limited to diabetes), motility disorders, hypertension, congestiveheart failure/cardiac capillary growth, hearing disorders, angina,syncope, vocal cord disorders, thyroid disorders, pulmonary disorders,and reproductive endocrine disorders (including infertility). In aparticular embodiment, the medical condition is epilepsy.

The implantable medical device (IMD) system of one embodiment of thepresent invention provides for module(s) that are capable of acquiring,storing, and processing one or more of various forms of data, such aspatient cardiac data or a cardiac parameter (e.g., heart rate, rate ofchange of heart rate, etc.), at least one value used to declare anunstable brain state of a patient, declarations of unstable brainstates, logs of timestamped cardiac data, cardiac parameters, andtherapy parameters. Therapy parameters may include, but are not limitedto, electrical signal parameters that define the therapeutic electricalsignals delivered by the IMD, medication parameters, and/or any othertherapeutic treatment parameter. Therapy parameters defining atherapeutic electrical signal may also include, but are not limited to,a current amplitude, a pulse width, an interburst period, a number ofpulses per burst, an interpulse interval, a burst duration, an on-time,and an off-time. “Therapy parameters” encompasses one or multipletreatment regimens (e.g., different electrical signals), wherein themultiple treatment regimens may differ in one or more therapyparameters.

Although not so limited, a system capable of implementing embodiments ofthe present invention is described below. FIG. 1 depicts a stylizedimplantable medical system (IMD) 100 for implementing one or moreembodiments of the present invention. An electrical signal generator 110is provided, having a main body 112 comprising a case or shell with aheader 116 for connecting to an insulated, electrically conductive leadassembly 122. The generator 110 is implanted in the patient's chest in apocket or cavity 145 formed by the implanting surgeon just below theskin, similar to the implantation procedure for a pacemaker pulsegenerator.

A nerve electrode assembly 125, preferably comprising a plurality ofelectrodes having at least an electrode pair, is conductively connectedto the distal end of the lead assembly 122, which preferably comprises aplurality of lead wires (one wire for each electrode). Each electrode inthe electrode assembly 125 may operate independently or alternatively,may operate in conjunction with the other electrodes. In one embodiment,the electrode assembly 125 comprises at least a cathode and an anode. Inanother embodiment, the electrode assembly comprises one or moreunipolar electrodes with the return electrode comprising a portion ofthe generator 110.

Lead assembly 122 is attached at its proximal end to connectors on theheader 116 of generator 110. The electrode assembly 125 may besurgically coupled to the vagus nerve 127 in the patient's neck or atanother location, e.g., near the patient's diaphragm or at theesophagus/stomach junction. Other (or additional) cranial nerves such asthe trigeminal and/or glossopharyngeal nerves may also be used as atarget for the electrical signal in particular alternative embodiments.In one embodiment, the electrode assembly 125 comprises a bipolarstimulating electrode pair 125-1, 125-2 (i.e., a cathode and an anode).Suitable electrode assemblies are available from Cyberonics, Inc.,Houston, Tex., USA as the Model 302 electrode assembly. However, personsof skill in the art will appreciate that many electrode designs could beused in the present invention. In one embodiment, the two electrodes arewrapped about the vagus nerve, and the electrode assembly 125 may besecured to the vagus nerve 127 by a spiral anchoring tether 128 such asthat disclosed in U.S. Pat. No. 4,979,511 issued Dec. 25, 1990 to ReeseS. Terry, Jr. and assigned to the same assignee as the instantapplication. Lead assembly 122 may be secured, while retaining theability to flex with movement of the chest and neck, by a sutureconnection 130 to nearby tissue (not shown).

In alternative embodiments, the electrode assembly 125 may comprise acardiac data sensor element. Alternatively, a cardiac data sensorelement may be contained in a separate sensing electrode assembly (notshown). One or more other sensor elements for other body parameters mayalso be included in the electrode assembly 125 or in a separate sensingelectrode assembly (not shown). For example, motion sensors orelectrodes may be used to sense respiration, and pressure sensors orneural activity may be used to sense blood pressure. Both passive andactive stimulation may be combined or delivered by a single IMDaccording to the present invention. Either or both modes may beappropriate to treat a specific patient under observation.

The electrical pulse generator 110 may be programmed with an externaldevice (ED) such as computer 150 using programming software known in theart. A programming wand 155 may be coupled to the computer 150 as partof the ED to facilitate radio frequency (RF) communication between thecomputer 150 and the pulse generator 110. The programming wand 155 andcomputer 150 permit non-invasive communication with the generator 110after the latter is implanted. In systems where the computer 150 usesone or more channels in the Medical Implant Communications Service(MICS) bandwidths, the programming wand 155 may be omitted to permitmore convenient communication directly between the computer 150 and thepulse generator 110.

The therapeutic electrical stimulation signal described herein may beused to treat a medical condition separately or in combination withanother type of treatment. For example, electrical signals according tothe present invention may be applied in combination with a chemicalagent, such as various drugs, to treat various medical conditions.Further, the electrical stimulation may be performed in combination withtreatment(s) relating to a biological or chemical agent. The electricalstimulation treatment may also be performed in combination with othertypes of treatment, such as magnetic stimulation treatment.

Turning now to FIG. 2, a block diagram depiction of the IMD 200 isprovided, in accordance with one illustrative embodiment of the presentinvention. The IMD 200 (which may be equivalent to generator 110 fromFIG. 1) may comprise a controller 210 capable of controlling variousaspects of the operation of the IMD 200. The controller 210 is capableof receiving internal data or external data and causing a stimulationunit 220 to generate and deliver an electrical signal to target tissuesof the patient's body for treating a medical condition. For example, thecontroller 210 may receive manual instructions from an operatorexternally, or may cause the electrical signal to be generated anddelivered based on internal calculations and programming. The controller210 is capable of affecting substantially all functions of the IMD 200.

The controller 210 may comprise various components, such as a processor215, a memory 217, etc. The processor 215 may comprise one or moremicrocontrollers, microprocessors, etc., capable of performing variousexecutions of software components. The memory 217 may comprise variousmemory portions where a number of types of data (e.g., internal data,external data instructions, software codes, status data, diagnosticdata, etc.) may be stored. The memory 217 may comprise one or more ofrandom access memory (RAM), dynamic random access memory (DRAM),electrically erasable programmable read-only memory (EEPROM), flashmemory, etc.

The IMD 200 may also comprise a stimulation unit 220 capable ofgenerating and delivering electrical signals to one or more electrodesvia leads. A lead assembly such as lead assembly 122 (FIG. 1) may becoupled to the IMD 200. Therapy may be delivered to the leads comprisingthe lead assembly 122 by the stimulation unit 220 based uponinstructions from the controller 210. The stimulation unit 220 maycomprise various circuitry, such as electrical signal generators,impedance control circuitry to control the impedance “seen” by theleads, and other circuitry that receives instructions relating to thedelivery of the electrical signal to tissue. The stimulation unit 220 iscapable of delivering an electrical signal over the leads comprising thelead assembly 122. It will be appreciated by persons of skill in the artthat some embodiments of the invention may comprise leadless stimulatorssuch as injectable microstimulators.

The IMD 200 may also comprise a power supply 230. The power supply 230may comprise a battery, voltage regulators, capacitors, etc., to providepower for the operation of the IMD 200, including delivering thetherapeutic electrical signal. The power supply 230 comprises a powersource that in some embodiments may be rechargeable. In otherembodiments, a non-rechargeable power source may be used. The powersupply 230 provides power for the operation of the IMD 200, includingelectronic operations and the electrical signal generation and deliveryfunctions. The power supply 230 may comprise a lithium/thionyl chloridecell or a lithium/carbon monofluoride (LiCFx) cell. Other battery typesknown in the art of implantable medical devices may also be used.

The IMD 200 may also comprise a communication unit 260 capable offacilitating communications between the IMD 200 and various devices. Inparticular, the communication unit 260 is capable of providingtransmission and reception of electronic signals to and from an externalunit 270, such as computer 150 and wand 155 that may comprise an ED(FIG. 1). The communication unit 260 may include hardware, software,firmware, or any combination thereof.

In one embodiment, the IMD 200 may also comprise a sensor 295 that iscapable of detecting various patient parameters. For example, the sensor295 may comprise hardware, software, firmware, or any combinationthereof that is capable of obtaining and/or analyzing data relating toone or more physiological parameters of the patient, such as at leastone cardiac parameter. In one embodiment, the lead assembly 122 andelectrode(s) 125 may function as the sensor 295. In another embodiment,the sensor 295 is a separate structure from the lead assembly 122 andelectrode(s) 125. In one embodiment, the sensor 295 may reside externalto the IMD 200 and the sensed results may be delivered to the IMD 200via wire, telemetry, or other techniques known in the art. Based uponthe data obtained by the sensor 295, an cardiac module 296 may determinethe at least one cardiac parameter.

In one embodiment, the sensor 295 may be capable of detecting a feedbackresponse from the patient. The feedback response may include a magneticsignal input, a tap input, a wireless data input to the IMD 200, etc.The feedback may be indicative of a pain and/or noxious threshold,wherein the threshold may be the limit of tolerance of discomfort for aparticular patient.

In one embodiment, the sensor 295 may be capable of sensing cardiac dataand the cardiac module 296 may be capable of determining at least onecardiac parameter of the patient from the sensed cardiac data. However,in another embodiment, a separate sensor 295 is not included, andsensing cardiac data of the patient may be performed via one or more ofthe electrodes 125(1), 125(2) and/or the shell 112 of the IMD 200.

Cardiac data may be sensed at any point in the patient's cardiac cycle.FIG. 3 shows an exemplary instance of the cardiac cycle in a humanbeing.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of an interbeat interval. The cardiac module 296may further be capable of determining a first cardiac parameterconsisting of an instantaneous heart rate, that is, the reciprocal of asingle interbeat interval, which may be normalized to a unit time, suchas one minute. For example, if the interbeat interval is determined asan R-R interval, and a single R-R interval is 800 msec, the reciprocalis 0.00125 msec⁻¹, or 1.25 sec⁻¹, or 75 min⁻¹ (75 BPM).

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of a moving average heart rate over a predeterminedtime period. The moving average heart rate may be a simple movingaverage, that is, the average of the reciprocal of n consecutiveinterbeat intervals, wherein n is an integer from 2 to about 20, such as3 to 10.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of a rate of change of the patient's heart rate,which may be determined from a series of values of either aninstantaneous heart rate or a moving average heart rate.

The cardiac module 296 may be capable of determining an elevation of apatient's heart rate above the patient's baseline heart rate. Forexample, a baseline heart rate may be defined as a 30-beat movingaverage heart rate, or longer moving average such as a 5 minute averageheart rate, and the elevation may be the difference between aninstantaneous heart rate and the baseline rate. Cardiac module 296 mayfurther be capable of determining a difference between a first movingaverage and a second moving average. The first and second movingaverages may be based upon a particular number of beats, for example a 3beat moving average and a 30 beat moving average, or upon particulartime periods, for example a 10 second moving average and a 5 minutemoving average. In another embodiment, cardiac module 296 may be capableof determining a first cardiac parameter consisting of a duration of anelevation of the patient's heart rate above the patient's baseline heartrate. The patient's baseline heart rate may be determined by a medicalprofessional at an initial calibration or subsequent recalibration ofthe IMD 200 or may be determined by the IMD 200 itself, such as a longterm moving average of the heart rate. The long term moving average canbe calculated with the exclusion of cardiac data from times recognized,either at the time or retrospectively, as being associated with anunstable brain state. “Unstable brain state” will be discussed below.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of a depression of the patient's heart rate belowthe patient's baseline heart rate.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of a duration of an elevation of a first movingaverage heart rate over a second moving average heart rate.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of an R-R interval.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of a PR segment interval.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of a PQ segment interval.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of a QRS interval.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of an ST segment interval.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of a statistical analysis heart parameter, such asa median, a standard deviation, or another statistical analysis valueknown to the person of ordinary skill in the art to be extractable orcalculable from a stream of cardiac data.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of the amplitude or magnitude of the P wave, Qwave, R wave, S wave, T wave, U wave, or any segment or interval betweenwaves; a change of the amplitude or magnitude of the wave or any segmentor interval between waves; or a rate of change of the amplitude ormagnitude of the wave or any segment or interval between waves. Theamplitude or magnitude of a segment or interval encompasses the absolutedifference in amplitude or magnitude of the waves defining the endpointsof the segment or interval and the relative difference in amplitude ormagnitude of the waves defining the endpoints of the segment orinterval, among other parameters.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of a spectral analysis heart parameter.

The cardiac module 296 may be capable of determining a first cardiacparameter consisting of a fractal analysis heart parameter.

In one embodiment, at least a first cardiac parameter is selected fromthe group consisting of an instantaneous heart rate, a moving averageheart rate over a predetermined time period, a ratio of a first movingaverage heart rate over a first predetermined time period and a secondmoving average heart rate over a second predetermined time period, arate of change of the patient's heart rate, an elevation of thepatient's instantaneous heart rate above a baseline heart rate, aduration of an elevation of the patient's heart rate above the patient'sbaseline heart rate, a depression of the patient's heart rate below thepatient's baseline heart rate, a duration of an elevation of a firstmoving average heart rate over a second moving average heart rate, anR-R interval, a PR segment interval, a PQ segment interval, a QRSinterval, an ST segment interval, a statistical analysis heartparameter, a spectral analysis heart parameter, a fractal analysis heartparameter, an interbeat interval, the amplitude or magnitude of the Pwave, Q wave, R wave, S wave, T wave, U wave, or any segment or intervalbetween waves; a change of the amplitude or magnitude of the wave or anysegment or interval between waves; or a rate of change of the amplitudeor magnitude of the wave or any segment or interval between waves, andtwo or more thereof.

The external unit 270 may be a device that is capable of programming theIMD 200 with parameters defining the electrical signal. In oneembodiment, the external unit 270 is a computer system capable ofexecuting a data-acquisition program. The external unit 270 may becontrolled by a healthcare provider, such as a physician, at a basestation in, for example, a doctor's office, or via telemetry from adoctor's office to a patient's home. In alternative embodiments, theexternal unit 270 may be controlled by a patient in a system. Inpatient-controlled systems, the external unit 270 may provide lesscontrol over the operation of the IMD 200 than another external unit 270controlled by a healthcare provider. Whether controlled by the patientor by a healthcare provider, the external unit 270 may be a computer,preferably a handheld computer or PDA, but may alternatively compriseany other device that is capable of electronic communications andprogramming, e.g., hand-held computer system, a PC computer system, alaptop computer system, a server, a personal digital assistant (PDA), anApple-based computer system, etc. The external unit 270 may uploadvarious parameters and program software into the IMD 200 for programmingthe operation of the IMD, and may also receive and download variousstatus conditions and other data from the IMD 200. Communicationsbetween the external unit 270 and the communication unit 260 in the IMD200 may occur via a wireless or other type of communication, representedgenerally by line 277 in FIG. 2. This may occur using, e.g., wand 155(FIG. 1) to communicate by RF energy with a generator 110.Alternatively, the wand may be omitted in some systems, e.g., systems inwhich external unit 270 operates in the MICS bandwidths.

In one embodiment, the external unit 270 may comprise a local databaseunit 255. Optionally or alternatively, the external unit 270 may also becoupled to a database unit 250, which may be separate from external unit270 (e.g., a centralized database wirelessly linked to a handheldexternal unit 270). The database unit 250 and/or the local database unit255 are capable of storing various data. This data may comprise cardiacdata acquired from a patient's body, at least one cardiac parameterderived from the cardiac data, other data acquired from a patient'sbody, at least one non-cardiac parameter derived from the other data, atleast a first value as will be discussed below, and/or therapy parameterdata. The database unit 250 and/or the local database unit 255 maycomprise data for a plurality of patients, and may be organized andstored in a variety of manners, such as in date format, severity ofdisease format, etc. The database unit 250 and/or the local databaseunit 255 may be relational databases in one embodiment. A physician mayperform various patient management functions using the external unit270, which may include obtaining and/or analyzing data from the IMD 200and/or data from the database unit 250 and/or the local database unit255. The database unit 250 and/or the local database unit 255 may storevarious patient data.

One or more of the blocks illustrated in the block diagram of the IMD200 in FIG. 2 may comprise hardware units, software units, firmwareunits, or any combination thereof. Additionally, one or more blocksillustrated in FIG. 2 may be combined with other blocks, which mayrepresent circuit hardware units, software algorithms, etc.Additionally, any number of the circuitry or software units associatedwith the various blocks illustrated in FIG. 2 may be combined into aprogrammable device, such as a field programmable gate array, an ASICdevice, etc.

Pulse shapes in electrical signals according to the present inventionmay include a variety of shapes known in the art including square waves,biphasic pulses (including active and passive charge-balanced biphasicpulses), triphasic waveforms, etc. In one embodiment, the pulsescomprise a square, biphasic waveform in which the second phase is acharge-balancing phase of the opposite polarity to the first phase.

Patient activation of an IMD 100 may involve use of an external controlmagnet for operating a reed switch in an implanted device, for example.Certain other techniques of manual and automatic activation ofimplantable medical devices are disclosed in U.S. Pat. No. 5,304,206 toBaker, Jr., et al., assigned to the same assignee as the presentapplication (“the '206 patent”). According to the '206 patent, means formanually activating or deactivating the electrical signal generator 110may include a sensor such as piezoelectric element mounted to the innersurface of the generator case and adapted to detect light taps by thepatient on the implant site. One or more taps applied in fast sequenceto the skin above the location of the electrical signal generator 110 inthe patient's body may be programmed into the implanted medical device100 as a signal for activation of the electrical signal generator 110.Two taps spaced apart by a slightly longer duration of time may beprogrammed into the IMD 100 to indicate a desire to deactivate theelectrical signal generator 110, for example. The patient may be givenlimited control over operation of the device to an extent determined bythe program dictated or entered by the attending physician. The patientmay also activate the IMD 100 using other suitable techniques orapparatus.

In one embodiment, the present invention relates to an implantablemedical device (IMD) to treat a medical condition in a patient,comprising an electrical signal generator 220; at least a firstelectrode 125-1 operatively coupled to the electrical signal generatorand to a vagus nerve 127 of the patient; a cardiac data sensing module295 capable of sensing cardiac data from the patient; an unstable brainstate declaration module 280 comprising a cardiac module 296 capable ofdetermining at least a first cardiac parameter based upon sensed cardiacdata from the patient; and a value setting module 282 for setting atleast a first value to be used by the unstable brain state declarationmodule 280; wherein the unstable brain state declaration module 280 iscapable of declaring an unstable brain state of a patient from said atleast a first cardiac parameter and said at least a first value and thevalue setting module 282 is capable of adjusting said at least a firstvalue.

The electrical signal generator 220 has been described above, as has theat least a first electrode 125-1 operatively coupled to the electricalsignal generator 220 and to a vagus nerve 127 of the patient and thecardiac data sensing module 295 capable of sensing cardiac data from thepatient.

The IMD 200 comprises an unstable brain state declaration module 280that, in turn, comprises a cardiac module 296 capable of determining atleast a first cardiac parameter based upon sensed cardiac data from thepatient. IMD 200 further comprises a value setting module 282 forsetting at least a first value to be used by the unstable brain statedeclaration module 280. The unstable brain state declaration module 280is capable of declaring an unstable brain state of a patient from saidat least a first cardiac parameter and said at least a first value.

An “unstable brain state” is used herein to refer to the state of thebrain during an epileptic seizure, the state of the brain during an aura(a perceptual disturbance which may occur before an epileptic seizure),the state of the brain during a post-ictal period after an epilepticseizure, or any other state of the brain associated with the increasedlikelihood of a seizure in the near future (within from about 1 sec toabout 12 hr, such as from about 5 sec to about 1 hr, such as from about10 sec to about 5 min). An unstable brain state may be attested by asomatic indication of an epileptic seizure, aura, or other unstablebrain state, but need not be. An unstable brain state may be attested byan electroencephalographic (EEG) indication of an epileptic seizure,aura, or other unstable brain state, but need not be. An unstable brainstate encompasses both a state after which an epileptic seizure ishighly likely or even inevitable, as well as a state in which anotherwise highly likely or inevitable epileptic seizure can be preventedby the application of a therapeutic electrical signal to nervous tissue,such as the brain or a cranial or peripheral nerve. However, an unstablebrain state may be declared with a reasonable degree of accuracy fromsomatic indications, and in a particular embodiment, from at least onecardiac parameter, in light of at least a first value.

The cardiac module 296 is capable of determining at least a firstcardiac parameter based upon sensed cardiac data from the patient, asdiscussed above.

The value setting module 282 sets at least a first value to be used bythe unstable brain state declaration module 280. The at least a firstvalue, along with the at least a first cardiac parameter determined bythe cardiac module 296, is used by the unstable brain state declarationmodule 280 to declare or not declare the occurrence of an unstable brainstate. For example, the at least a first cardiac parameter may be amoving average of the patient's heart rate (by way of example only,having a baseline value of 60-75 BPM) and the at least a first value maybe a heart rate threshold value (by way of example only, 120 BPM). At apredetermined sampling rate, by way of example, from about 100 times persecond to about once per five seconds, the cardiac module 296 determinesthe moving average of the patient's heart rate and the unstable brainstate declaration module 280 compares the moving average of thepatient's heart rate to the heart rate threshold value. If, by way ofexample only, the moving average of the patient's heart rate is 125 BPM,which is greater than the heart rate threshold value of this example,the unstable brain state declaration module 280 declares that anunstable brain state has occurred. If, by way of example only, themoving average of the patient's heart rate is 80 BPM, which is less thanthe heart rate threshold value of this example, the unstable brain statedeclaration module 280 does not declare an unstable brain state to haveoccurred.

In one embodiment, the memory 217 is capable of storing a timestampassociated with a declaration of an unstable brain state by the unstablebrain state declaration module 280. The memory 217 may also be capableof storing a time series of the at least one cardiac parameter and/orthe at least a first value. The unstable brain state declaration module280, or another module in the IMD 200 or in an apparatus incommunication with the IMD 200 (such as the computer 150), may create alog of times at which a patient experiences an unstable brain state.

In addition to the heart rate threshold value discussed above, the atleast a first value may also comprise a minimum duration of an elevationof heart rate, a threshold rate of change of heart rate, or anycombination of cardiac and/or non-cardiac values. The at least a firstvalue may be a logical or Boolean value, a set of logical or Booleanvalues, or a combination of one or more logical or Boolean values andone or more alphanumeric values. In embodiments in which the IMD 200collects multiple parameters, such as multiple cardiac parameters, orboth at least one cardiac parameter and at least one non-cardiacparameter (discussed below), the at least a first value may alsocomprise either or both of weightings for each of the multipleparameters, and logical relationships between each of the multipleparameters.

The value setting module 282 is capable of adjusting the at least firstvalue. The determination of the different value may be made by a medicalprofessional, by the patient, or by the IMD 200 itself. For example,continuing the above example, if the patient experienced a seizurecorrelated with an increase in the patient's heart rate to 115 BPM(below the heart rate threshold value of 120 BPM, and hence, with nodeclaration of an unstable brain state), the value setting module 282may adjust the heart rate threshold value to 115 BPM, 110 BPM, or someother value. Such adjustment would render the unstable brain statedetermination module more likely to declare an unstable brain state.

Alternatively in the above example, if the patient experienced a heartrate above the heart rate threshold value of 120 BPM, and hence, anunstable brain state was declared, but the patient's elevated heart ratewas caused by volitional physical exertion, an intense emotionalresponse, or another cause not associated with an unstable brain state,the value setting module 282 may adjust the heart rate threshold valueto 125 BPM, 130 BPM, or some other value. Such adjustment would renderthe unstable brain state determination module less likely to declare anunstable brain state.

Continuing with the above example, the decision to adjust the heart ratethreshold may be made by a medical professional or by the patient, suchas at a time shortly after the seizure or at a later time when a log ofthe patient's at least one cardiac parameter is analyzed. In otherwords, in this embodiment, the value setting module 282 is capable ofadjusting the at least a first value in response to a user request toadjust the at least a first value.

The present invention gives a user, such as a patient or a medicalprofessional, great flexibility in deciding how to respond touncertainty inherent in the assessment of whether or not an unstablebrain state has occurred. A user may set the at least a first value suchthat the unstable brain state declaration module 280 declares unstablebrain states with any desired level of aggressiveness or certainty. Forexample, a user may accept a high “false positive” rate and want theunstable brain state declaration module 280 to declare every putativeunstable brain state; contrarily, a user may desire a low “falsepositive” rate and want the unstable brain state declaration module 280to only declare an unstable brain state with very high certainty, oreven to declare only particular kinds of unstable brain states, such asrelatively severe epileptic seizures as opposed to all seizures. Thus,the present invention provides the user a great deal of flexible controlover the stringency of declarations of unstable brain states.

Having the benefit of the present disclosure, the person of ordinaryskill in the art would be able to set and adjust the at least a firstvalue as a matter of routine experimentation.

In one embodiment, the adjustment may be made by a unit of the valuesetting module 282 on a determination of an unstable brain state fromother data, such as other cardiac data (e.g., an elevation of heart rateabove the patient's baseline heart rate for a predetermined oradjustable duration, or a difference between a first moving average anda second moving average, among others) or other data (e.g., an outputfrom an accelerometer measuring acceleration of the patient's limbs,torso, or head, wherein the output is indicative of a seizure; or anoutput from electromyography of one or more muscles, wherein the outputis indicative of a seizure; among others).

As discussed above, the value setting module 282 is capable of adjustingthe at least a first value to render the unstable brain statedeclaration module 280 less likely to declare an unstable brain state.Rendering the unstable brain state declaration module 280 less likely todeclare an unstable brain state may lead to fewer overall declarationsof unstable brain states or a delay in a declaration of an unstablebrain state, among other possible outcomes. This may be desirable, forexample, when a healthcare provider desires to use the IMD as a seizurediary and wishes to avoid declaring an unstable brain state unless anduntil an epileptic seizure actually occurs, or when the device respondsto the declaration of an unstable brain state by providing vagus nervestimulation, but the patient has difficulty tolerating the therapy thusprovided. Adjusting the first value to reduce the likelihood of adeclaration of an unstable brain state may lead to fewer falsedeclarations of unstable brain states. Such an adjustment may, however,risk actual occurrences of unstable brain states that are not declared,i.e., may lead to more “false negatives,” with an associated increasedrisk that an epileptic seizure would occur without therapy beingadministered or being administered late.

As stated above, rendering the unstable brain state declaration module280 less likely to declare an unstable brain state may in someembodiments lead to a delay in a declaration of an unstable brain state.A delay in declaration may be advantageous by giving greater certaintyto the patient or physician that a declaration is made when an unstablebrain state is actually occurring. However, this does represent atrade-off against earlier declaration of an unstable brain state. Forexample, if the declaration of an unstable brain state is followed by atherapeutic electrical signal intended to intervene in the unstablebrain state, a delay in declaration may lead to a shorter time windowfor delivering the therapeutic electrical signal or a requirement forthe therapeutic electrical signal to have a higher amplitude, frequency,on-time, or other parameter than would be required if the therapy wereprovided sooner.

Similarly, as discussed above, the value setting module 282 is capableof adjusting the at least a first value to render the unstable brainstate declaration module 280 more likely to declare an unstable brainstate. Rendering the unstable brain state declaration module 280 morelikely to declare an unstable brain state may lead to more overalldeclarations of unstable brain states or faster declaration of anunstable brain state, among other possible outcomes. Such an adjustmentmay be desirable where a patient experiences severe epileptic seizures,and it is important to intervene with a therapy such as vagus nervestimulation as early as possible with the goal of avoiding or reducingthe severity of the seizure, even if some occasions of “false positives”occur in which a seizure would not have occurred even absent the therapyintervention. Adjusting the first value to increase the likelihood of adeclaration of the occurrence of an unstable brain state may lead tofewer unstable brain states actually leading to seizures, though one ormore false declarations of unstable brain states may result, along withan increase in unnecessary therapy interventions.

As should be apparent to the person of ordinary skill in the art,rendering the unstable brain state declaration module 280 more likely todeclare an unstable brain state may lead to a faster declaration of anunstable brain state. A faster declaration may be advantageous by givinga longer time window for delivering a therapeutic electrical signal orby allowing the therapeutic electrical signal to have a lower amplitude,frequency, on-time, or other parameter than if the therapy were providedlater. However, this does represent a trade-off against laterdeclaration of an unstable brain state. For example, faster declarationof an unstable brain state may reduce the certainty to the patient orphysician that a declaration is made when an unstable brain state isactually occurring.

Alternatively or in addition to use of at least one cardiac parameterand at least a first value to declare an unstable brain state, in oneembodiment, the unstable brain state declaration module 280 maydetermine at least one non-cardiac parameter and at least a secondvalue. The at least one non-cardiac parameter and at least a secondvalue may either be used in a calculation to confirm or deny adeclaration of an unstable brain state based on the at least one cardiacparameter and the at least a first value, or may be used in combinationwith the at least one cardiac parameter and the at least a first valuein making the declaration of an unstable brain state. Alternatively orin addition, the at least one non-cardiac parameter and at least asecond value may be used to make a “shadow” or putative declaration ofan unstable brain state, against which declarations of unstable brainstates using the at least one cardiac parameter can be compared by amedical professional or the IMD to assist in adjusting the at least afirst value. Returning to the above example, wherein the at least afirst value is a heart rate threshold value, the “shadow” declaration ofan unstable brain state can be the basis for a decision to raise orlower the heart rate threshold value.

In one embodiment, the unstable brain state declaration module 280 mayfurther comprise a non-cardiac parameter detection module (not shown)capable of detecting an activity level of the patient.

In one embodiment, the unstable brain state declaration module 280 mayfurther comprise a non-cardiac parameter detection module capable ofdetecting an output of an accelerometer. The accelerometer may be wornon the patient's person or implanted in the patient's body.

In one embodiment, the unstable brain state declaration module 280 mayfurther comprise a non-cardiac parameter detection module capable ofdetecting a catamenial cycle. The parameter detection module of thisembodiment may detect the presence of hormones associated with thecatamenial cycle, the patient's basal temperature, the patient's or herphysician's observation of events indicative of various points in hercatamenial cycle, or other data indicative of the patient's catamenialcycle.

In one embodiment, the unstable brain state declaration module 280 mayfurther comprise a non-cardiac parameter detection module capable ofdetecting the time of day. The parameter detection module of thisembodiment may be a clock or a module capable of querying a clock forthe current time.

In one embodiment, the unstable brain state declaration module 280 mayfurther comprise a non-cardiac parameter detection module capable ofdetecting an indicator of the patient's sleep state. Exemplaryindicators of the patient's sleep include electroencephalogram (EEG)signals associated with sleep and rapid eye movements associated withREM sleep, among others.

In one embodiment, the unstable brain state declaration module 280 mayfurther comprise a non-cardiac parameter detection module capable ofdetecting an inclination of the patient's body.

In one embodiment, the unstable brain state declaration module 280 mayfurther comprise a non-cardiac parameter detection module capable ofdetecting a dilation of a pupil of the patient.

In one embodiment, the unstable brain state declaration module 280 mayfurther comprise a non-cardiac parameter detection module capable ofdetecting the patient's body temperature.

In one embodiment, the unstable brain state declaration module 280 mayfurther comprise a non-cardiac parameter detection module capable ofdetecting the patient's blood pressure.

In one embodiment, the unstable brain state declaration module 280 mayfurther comprise a non-cardiac parameter detection module capable ofdetecting the patient's electroencephalogram (EEG).

In one embodiment, the unstable brain state declaration module 280 mayfurther comprise a non-cardiac parameter detection module capable ofdetecting at least one non-cardiac parameter selected from the groupconsisting of an activity level of the patient, an output of anaccelerometer, a catamenial cycle, the time of day, an indicator of thepatient's sleep state, an inclination of the patient's body, a dilationof a pupil of the patient, the patient's body temperature, the patient'sblood pressure, and the patient's electroencephalogram (EEG).

As stated above, in embodiments wherein the unstable brain statedeclaration module 280 uses multiple parameters, the at least a firstvalue may relate to weightings of or logical relationships between themultiple parameters. For example, if an accelerometer (A) has beeninactive and heart rate (R) begins to increase rapidly, the at least afirst value may be a logical value boolHeartRateIncreaseWithoutActivityset to true, and the unstable brain state declaration module 280 maydeclare an unstable brain state from the logical value being true.However if an accelerometer indicates high activity level and then heartrate begins to increase rapidly, a logical valueboolHeartRateIncreaseWithoutActivity may be set to false, and theunstable brain state declaration module 280 may not declare an unstablebrain state from the logical value being false. More aggressive usersmay desire a logical value boolHeartRateIncrease=true or one of a pairof logical values (boolHeartRateIncrease=true or boolActivity=true) tobe sufficient for the unstable brain state declaration module 280 todeclare an unstable brain state.

In embodiments wherein the unstable brain state declaration module 280further comprises a non-cardiac parameter detection module, the valuesetting module 282 may be capable of setting at least a second value,and the unstable brain state declaration module 280 is capable ofdeclaring an unstable brain state of the patient from both said at leastone non-cardiac parameter and said at least a second value. For example,the second value may be an acceleration threshold of a limb; if anaccelerometer implanted in the limb reports an acceleration greater thanthe acceleration threshold, the unstable brain state declaration module280 in this example may declare an unstable brain state on theassumption the limb acceleration results from uncontrolled contractionof one or more skeletal muscles in the limb.

In one embodiment, the at least one non-cardiac parameter and the atleast a second value can be used by the value setting module 282 toadjust the at least a first value, the at least a second value, or both.Alternatively or in addition, in embodiments wherein the memory 217 iscapable of storing a timestamp at which a patient experienced anunstable brain state declared by the unstable brain state declarationmodule 280, the timestamp or a log of timestamps can be used by thevalue setting module 282 to adjust the at least a first value, the atleast a second value, or both. In other words, in one embodiment thevalue setting module 282 is capable of adjusting the at least a firstvalue, the at least a second value, or both based upon at least onefactor selected from the group consisting of a timestamp at which apatient experienced an unstable brain state, cardiac data associatedwith a timestamp at which a patient experienced an unstable brain state,an activity level of the patient, an output of an accelerometer, acatamenial cycle, the time of day, an indicator of the patient's sleep,an inclination of the patient's body, a dilation of a pupil of thepatient, the patient's body temperature, the patient's blood pressure,and the patient's electroencephalogram (EEG).

A patient may experience changes in the frequency of unstable brainstates over various periods of time. For example, a patient may have anincreased frequency of unstable brain states during certain hours of theday, certain days of the week or month, certain seasons of the year, orover longer periods of time as the patient's disease state changes. Inone embodiment, the value setting module 282 is capable of analyzing alog of times at which a patient experiences an unstable brain state todetermine at least a first period when the patient has an increasedfrequency of unstable brain states, and adjusting the at least a firstvalue to render the unstable brain state declaration module 280 morelikely to declare an unstable brain state during said at least a firstperiod. The first period may be less than one day. In other embodiments,the first period may be less than one week, less than one month, or lessthan one year.

The value setting module 282 may comprise other modules than thosedescribed above.

The IMD 200 described above, and methods described herein, are useful inproviding a user, such as a patient or a medical professional, withinformation regarding the patient's unstable brain states. Suchinformation may assist the patient and the medical professional inimproving the patient's treatment regimen or improving the patient'squality of life. The information regarding the patient's unstable brainstates may include an alert to the patient and/or his caregiver that anepileptic seizure is likely, giving the patient and/or his caregiversome time to prepare for the epileptic seizure and its aftermath.

In one embodiment, the electrical signal generator of the implantablemedical device is capable of generating and delivering at least a firstelectrical signal through at least the first electrode to the vagusnerve if an unstable brain state has not been declared, and generatingand delivering at least a second electrical signal through at least thefirst electrode to the vagus nerve if an unstable brain state has beendeclared. The first electrical signal can be a conventional VNS signalfor the chronic treatment of epilepsy. The second electrical signal canbe an active VNS signal for the prevention or reduction in severity ofan epileptic seizure. The second electrical signal can have a greaterpulse amplitude, a wider pulse width, a higher pulse frequency, agreater number of pulses per burst, a higher on time/off time ratio, ortwo or more thereof, relative to a conventional VNS signal. Such asecond electrical signal would consume more electrical power than aconventional VNS signal and could be attenuated by adaptation thereto byneurons of the vagus nerve if the second electrical signal werecontinuously applied. However, if the second electrical signal wereapplied only when an unstable brain state is declared, the duration ofapplication would be expected to be short enough that adaptation theretowould be unlikely, and the increased consumption of electrical powerwould be likely to be offset by a reduction in the number, severity, orboth of the patient's seizures and an accompanying improvement in thepatient's quality of life. The adjustability of the at least a firstvalue would allow considerations of IMD battery life to be included inthe actions of the value setting module 282.

In one embodiment, as shown in FIG. 4, the present invention relates toa method 400 of treating a medical condition in a patient using animplantable medical device 200, comprising providing 410 an electricalsignal generator; providing 420 at least a first electrode operativelycoupled to the electrical signal generator and to a vagus nerve of thepatient; sensing 430 cardiac data of the patient; determining 440 atleast a first cardiac parameter based upon said cardiac data; setting450 at least a first value; declaring 460 an unstable brain state of apatient from said at least a first cardiac parameter and said at least afirst value; and adjusting 470 the at least a first value.

In one embodiment, the method can further comprise generating andapplying 462 a first electrical signal to the vagus nerve if an unstablebrain state has not been declared, and generating and applying 464 asecond electrical signal to the vagus nerve if an unstable brain statehas been declared. FIG. 5 shows this embodiment.

In one embodiment, sensing 430 cardiac data comprises sensing at leastone of a P wave, an Q wave, a QR complex, an R wave, an S wave, a QRScomplex, a T wave, and a U wave, and wherein said at least a firstcardiac parameter comprises at least one of an instantaneous heart rate,a moving average heart rate over a predetermined time period, a ratio ofa first moving average heart rate over a first predetermined time periodand a second moving average heart rate over a second predetermined timeperiod, a rate of change of the patient's heart rate, an elevation ofthe patient's instantaneous heart rate above a baseline heart rate, aduration of an elevation of the patient's heart rate above the patient'sbaseline heart rate, a duration of an elevation of a first movingaverage heart rate over a second moving average heart rate, an R-Rinterval, a P-P interval, a PR segment interval, a PQ segment interval,a QRS interval, an ST segment interval, a statistical analysis heartparameter, a spectral analysis heart parameter, a fractal analysis heartparameter, and two or more thereof.

In one embodiment, adjusting 470 the at least a first value occurs inresponse to a user request to adjust the first value.

In one embodiment, adjusting 470 the at least a first value comprisesrendering declaring an unstable brain state less likely and/or lessquickly. In another embodiment, adjusting 470 the at least a first valuecomprises rendering declaring an unstable brain state more likely and/ormore quickly.

In one embodiment, the method further comprises storing a timestampassociated with declaring an unstable brain state. In one furtherembodiment, adjusting the at least a first value is based upon aplurality of the timestamps. In another further embodiment, the methodfurther comprises storing a time series of the at least a first cardiacparameter.

In one embodiment, the method further comprises determining at least afirst period when the patient has an increased frequency of unstablebrain states, and adjusting the at least a first value to renderdeclaring an unstable brain state more likely during said at least afirst period.

In one embodiment, the present invention relates to a computer readableprogram storage device encoded with instructions that, when executed bya computer, performs a method of treating a medical condition in apatient using an implantable medical device, comprising; sensing cardiacdata of the patient; determining at least a first cardiac parameterbased upon said cardiac data; setting at least a first value; declaringan unstable brain state of a patient from said at least a first cardiacparameter and said at least a first value; and adjusting the at least afirst value.

The method executed by the computer may provide a log of unstable brainstates or an alert of an unstable brain state.

In one embodiment of the computer readable program storage device, themethod further comprises, if an unstable brain state is not declared,instructing an electrical signal generator to generate and deliver afirst electrical signal through at least the first electrode to thevagus nerve of the patient, and if an unstable brain state is declared,instructing an electrical signal generator to generate and deliver asecond electrical signal through at least the first electrode to thevagus nerve of the patient.

Using embodiments of the present invention, a therapeutic regimencomprising neurostimulation may be enhanced and optimized. Using certainembodiments, data either directly or indirectly associated with an acuteincident of a medical condition may be collected, in order to inform thepatient and/or his physician about the severity, progression, orremission of the medical condition.

All of the methods and apparatuses disclosed and claimed herein may bemade and executed without undue experimentation in light of the presentdisclosure. While the methods and apparatus of this invention have beendescribed in terms of particular embodiments, it will be apparent tothose skilled in the art that variations may be applied to the methodsand apparatus and in the steps, or in the sequence of steps, of themethod described herein without departing from the concept, spirit, andscope of the invention, as defined by the appended claims. It should beapparent that the principles of the invention may be applied to selectedcranial nerves other than, or in addition to, the vagus nerve to achieveparticular results in treating patients having epilepsy, depression, orother medical conditions.

The particular embodiments disclosed above are illustrative only as theinvention may be modified and practiced in different but equivalentmanners apparent to those skilled in the art having the benefit of theteachings herein. Furthermore, no limitations are intended to thedetails of construction or design herein shown other than as describedin the claims below. It is, therefore, evident that the particularembodiments disclosed above may be altered or modified the protectionsought herein is as set forth in the claims below.

1. An implantable medical device (IMD) to treat a medical condition in apatient, comprising: an electrical signal generator; at least a firstelectrode operatively coupled to the electrical signal generator and toa vagus nerve of the patient; a cardiac data sensing module capable ofsensing cardiac data from the patient; an unstable brain statedeclaration module comprising a cardiac module capable of determining atleast a first cardiac parameter based upon sensed cardiac data from thepatient; and a value setting module for setting at least a first valueto be used by the unstable brain state declaration module; wherein: theunstable brain state declaration module is capable of declaring anunstable brain state of a patient from said at least a first cardiacparameter and said at least a first value, and the value setting moduleis capable of adjusting said at least a first value.
 2. The implantablemedical device of claim 1, wherein the cardiac module is capable ofdetermining at least a second cardiac parameter based upon sensedcardiac data from the patient, and the unstable brain state declarationmodule is capable of declaring an unstable brain state of a patient fromsaid at least a first cardiac parameter, said at least a second cardiacparameter, and said at least a first value.
 3. The implantable medicaldevice of claim 1, wherein the electrical signal generator is capable ofgenerating and delivering at least a first electrical signal through atleast the first electrode to the vagus nerve if an unstable brain statehas not been declared, and generating and delivering at least a secondelectrical signal through at least the first electrode to the vagusnerve if an unstable brain state has been declared.
 4. The implantablemedical device of claim 1, wherein the value setting module is capableof adjusting at least the first value in response to a user request toadjust at least the first value.
 5. The implantable medical device ofclaim 1, wherein the value setting module is capable of adjusting the atleast a first value to render the unstable brain state declarationmodule less likely to declare an unstable brain state.
 6. Theimplantable medical device of claim 1, wherein the value setting moduleis capable of adjusting the at least a first value to render theunstable brain state declaration module more likely to declare anunstable brain state.
 7. The implantable medical device of claim 1,wherein the at least a first cardiac parameter is selected from thegroup consisting of an instantaneous heart rate, a moving average heartrate over a predetermined time period, a ratio of a first moving averageheart rate over a first predetermined time period and a second movingaverage heart rate over a second predetermined time period, a rate ofchange of the patient's heart rate, an elevation of the patient'sinstantaneous heart rate above a baseline heart rate, a duration of anelevation of the patient's heart rate above the patient's baseline heartrate, a depression of the patient's heart rate below the patient'sbaseline heart rate, a duration of an elevation of a first movingaverage heart rate over a second moving average heart rate, an R-Rinterval, a PR segment interval, a PQ segment interval, a QRS interval,an ST segment interval, a statistical analysis heart parameter, aspectral analysis heart parameter, a fractal analysis heart parameter,an interbeat interval, the amplitude or magnitude of the P wave, Q wave,R wave, S wave, T wave, U wave, or any segment or interval betweenwaves; a change of the amplitude or magnitude of the wave or any segmentor interval between waves; or a rate of change of the amplitude ormagnitude of the wave or any segment or interval between waves, and twoor more thereof.
 8. The implantable medical device of claim 1, whereinsaid unstable brain state declaration module further comprises anon-cardiac parameter detection module capable of detecting at least onenon-cardiac parameter selected from the group consisting of an activitylevel of the patient, an output of an accelerometer, a catamenial cycle,the time of day, an indicator of the patient's sleep state, aninclination of the patient's body, a dilation of a pupil of the patient,the patient's body temperature, the patient's blood pressure, and thepatient's electroencephalogram (EEG), wherein said value setting moduleis capable of setting at least a second value, and wherein said unstablebrain state declaration module is capable of declaring an unstable brainstate of the patient from both said at least one non-cardiac parameterand said at least a second value.
 9. The implantable medical device ofclaim 1, further comprising a memory capable of storing a timestampassociated with a declaration of an unstable brain state.
 10. Theimplantable medical device of claim 9, wherein said value setting moduleis capable of adjusting the at least a first value based upon at leastone factor selected from the group consisting of a timestamp at which apatient experienced an unstable brain state, cardiac data associatedwith a timestamp at which a patient experienced an unstable brain state,an activity level of the patient, an output of an accelerometer, acatamenial cycle, the time of day, an indicator of the patient's sleepstate, an inclination of the patient's body, a dilation of a pupil ofthe patient, the patient's body temperature, the patient's bloodpressure, and the patient's electroencephalogram (EEG).
 11. Theimplantable medical device of claim 8, further comprising a memorycapable of storing said at least one non-cardiac parameter, and whereinsaid value setting module is capable of adjusting said at least a secondvalue based upon at least one factor selected from the group consistingof a timestamp at which a patient experienced an unstable brain state,cardiac data associated with a timestamp at which a patient experiencedan unstable brain state, an activity level of the patient, an output ofan accelerometer, a catamenial cycle, the time of day, an indicator ofthe patient's sleep, an inclination of the patient's body, a dilation ofa pupil of the patient, the patient's body temperature, the patient'sblood pressure, and the patient's electroencephalogram (EEG).
 12. Theimplantable device of claim 9, wherein said value setting module iscapable of analyzing a log of times at which a patient experiences anunstable brain state to determine at least a first period when thepatient has an increased frequency of unstable brain states, andadjusting the at least a first value to render the unstable brain statedeclaration module more likely to declare an unstable brain state duringsaid at least a first period.
 13. The implantable device of claim 12,wherein the first period is less than one day.
 14. A method of treatinga medical condition in a patient using an implantable medical device,comprising: providing an electrical signal generator, providing at leasta first electrode operatively coupled to the electrical signal generatorand to a vagus nerve of the patient; sensing cardiac data of thepatient; determining at least a first cardiac parameter based upon saidcardiac data; setting at least a first value; declaring an unstablebrain state of a patient from said at least a first cardiac parameterand said at least a first value; and adjusting said at least a firstvalue.
 15. The method of claim 14, further comprising, generating andapplying a first electrical signal to the vagus nerve if an unstablebrain state has not been declared, and generating and applying a secondelectrical signal to the vagus nerve if an unstable brain state has beendeclared.
 16. The method of claim 14, wherein sensing cardiac datacomprises sensing at least one of a P wave, an Q wave, a QR complex, anR wave, an S wave, a QRS complex, a T wave, and a U wave, and whereinsaid at least a first cardiac parameter comprises at least one of aninstantaneous heart rate, a moving average heart rate over apredetermined time period, a ratio of a first moving average heart rateover a first predetermined time period and a second moving average heartrate over a second predetermined time period, a rate of change of thepatient's heart rate, an elevation of the patient's instantaneous heartrate above a baseline heart rate, a duration of an elevation of thepatient's heart rate above the patient's baseline heart rate, a durationof an elevation of a first moving average heart rate over a secondmoving average heart rate, an R-R interval, a P-P interval, a PR segmentinterval, a PQ segment interval, a QRS interval, an ST segment interval,a statistical analysis heart parameter, a spectral analysis heartparameter, a fractal analysis heart parameter, the amplitude ormagnitude of the P wave, Q wave, R wave, S wave, T wave, U wave, or anysegment or interval between waves; a change of the amplitude ormagnitude of the wave or any segment or interval between waves; or arate of change of the amplitude or magnitude of the wave or any segmentor interval between waves, and two or more thereof.
 17. The method ofclaim 14, wherein adjusting the at least a first value occurs inresponse to a user request to adjust the first value.
 18. The method ofclaim 14, wherein adjusting the at least a first value comprisesrendering declaring an unstable brain state less likely.
 19. The methodof claim 14, wherein adjusting the at least a first value comprisesrendering declaring an unstable brain state more likely.
 20. The methodof claim 14, further comprising storing a timestamp associated withdeclaring an unstable brain state.
 21. The method of claim 20, furthercomprising storing a time series of the at least a first cardiacparameter.
 22. The method of claim 20, wherein adjusting the at least afirst value is based upon a plurality of said timestamps.
 23. The methodof claim 20, further comprising determining at least a first period whenthe patient has an increased frequency of unstable brain states, andadjusting the at least a first value to render declaring an unstablebrain state more likely during said at least a first period.
 24. Acomputer readable program storage device encoded with instructions that,when executed by a computer, performs a method of treating a medicalcondition in a patient using an implantable medical device, comprising:sensing cardiac data of the patient; determining at least a firstcardiac parameter based upon said cardiac data; setting at least a firstvalue; declaring an unstable brain state of a patient from said at leasta first cardiac parameter and said at least a first value; and adjustingsaid at least a first value.
 25. The computer readable program storagedevice of claim 24, wherein the method further comprises: if an unstablebrain state is not declared, instructing an electrical signal generatorto generate and deliver a first electrical signal through at least thefirst electrode to the vagus nerve of the patient, and if an unstablebrain state is declared, instructing an electrical signal generator togenerate and deliver a second electrical signal through at least thefirst electrode to the vagus nerve of the patient.